In the field of obstetrics, one of the most important problems is the management of preterm labor and premature birth as they represent a major cause of perinatal morbidity and mortality.
In recent years, strong evidence has accumulated indicating that the hormone oxytocin plays a major role in initiating labor in mammals, notably in humans. Thereby, it is assumed that oxytocin exerts said effect in a direct as well as an indirect way, by contracting the uterine myometrium and by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may furthermore play a role in the cervical ripening process.
In parturition, the high circulating concentrations of progesterone induce uterine quiescence while the uterus acquires contractile ability. Shortly before term, plasma progesterone concentrations fall, oxytocin receptor expression in the uterus increases markedly, and uterine contractile activity increases. At term, the contractions rise to a crescendo, resulting in delivery as a result of two interacting positive feedback loop. The first is a local uterine loop: within the uterus itself prostaglandins and other uterotonic factors are produced and released in response to uterine contractions. The second loop involves the hypothalamus: in response to uterine contractions and vaginal and cervical distension, magnocellular oxytocin neurons in the hypothalamus increase their activity resulting in the release of oxytocin from their axon terminals in the posterior pituitary; the released oxytocin acts upon the uterus both to stimulate the further production of prostaglandins and to contribute further to the contractions of the uterus. (Journal of Endocrinology 157, p. 343-359 (1998) by J. A Russell and al.).
For the treatment of preterm labor, several approaches have been considered such as the use of magnesium sulfate, ethanol or therapeutic agents acting as α2 adrenergic agonists or oxytocin antagonists:                With the use of magnesium sulfate, it has been observed that plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable notably when the renal function is impaired.        Ethanol is effective in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress. Also, ethanol is assumed to have a negative impact on the fetus.        The β2-adrenergic receptor generally causes an inhibitory action within the cells wherein it is expressed (muscles, heart, uterus etc). β2-adrenergic agonists are used to activate said inhibitory action of the receptor. Hence, β2-adrenergic agonists are sympathomimetics which—among others—inhibit uterine contractility. Known β2-adrenergic agonists for the treatment of preterm labor are Ritodrine, Terbutaline and Albuterol.        Oxytocin antagonists: Oxytocin (OT) is a peptide hormone causing the contraction of the uterus of mammals during labor. Oxytocin (OT) receptors increase dramatically during the course of pregnancy. The concentration of OT receptors has been shown to correlate with spontaneous uterine activity. In the last few years, a number of papers have suggested that the hormone oxytocin may be a physiological initiator of labor in several mammalian species including humans. Furthermore, oxytocin is believed to exert this effect in two different parts, either by directly contracting the uterine myometrium and by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. Therefore, by blocking oxytocin, the direct (contractile) and indirect (enhanced prostaglandin synthesis) effects of oxytocin on the uterus may be achieved.        
Prostaglandins (PGs), more particularly prostaglandin F2α (PGF2α), play a key role in the normal physiology of several tissues including ovary, oviduct, uterus, testis, lung and possibly eye and heart and is implicated in reproductive functions such as ovulation, luteolysis and parturition. It is well known that parturition is initiated when prostaglandin F2α interacts with FP (Prostaglandin F receptor) in ovarian luteal cells of the pregnant mice to induce luteolysis. (Science vol. 277, p. 681-687 (1997) by Yuhihiko Sugimoto et al). Actions of PGF2α are mediated by the PGF receptor (FP), which is a heterotrimeric guanosine triphosphate—binding protein (G protein)—coupled rhodopsin type receptor specific to this PG (Science vol. 277, p. 681-83 (1998) by Yuhihiko Sugimoto et al.).
These prostaglandins belong to a group of eicosanoids that are produced by the enzymatic activity of cyclooxygenase. Together with the thromboxanes, prostaglandins constitute the prostanoid subgroup of the eicosanoids. Prostaglandins (PGs) mediate various physiological processes such as fever generation and inflammation. Aspirin and related drugs act through inhibition of PG biosynthesis.
PGF2α is synthesized, to varying degrees, by almost every tissue in the body and is a stimulant of several different types of physiological functions including granulose lutein cell death, myometrial smooth muscle contraction, Leydig cell testosterone synthesis regulation, regulation of oviductal cilia beating, bronchoconstriction, and bone metabolism. They are synthesized in fetal and maternal membranes and act to ripen the cervix and contract the myometrium. PGF2α is a major prostaglandin for enhancing uterine contractility.
Specific prostaglandin receptors (EP1, EP2, EP4 and FP) are expressed in the human myometrium Activation of EP2 and EP4 receptors results in smooth muscle relaxation whereas activation of the PGF2α-selective receptor (FP receptor) results in contraction. Indeed, the prostaglandin F2α receptor acts via a G protein-coupled receptor, coupled to activation of phospholipase C and increases in IP3 that release Ca2+ from intracellular stores. The increases in intracellular calcium that ensue lead to increased contraction of smooth muscle via activation of myosin light chain kinase. Also, it is known that mice lacking the FP receptor have normal fertility but no labor at term. However healthy pups were delivered by cesarean cut. One of the most important roles of PGF2α is in reproductive biology as a luteolytic agent. In the non-pregnant state, at the end of the luteal phase, increased pulsatile serum levels of PGF2α (of uterine origin) cause apoptotic cell death of the granulosam lutein cells (Res. Reprod. 16:1-2 (1984) by McCracken).
There is recent evidence for up-regulation of the contractile FP receptor with the onset and during progression of labor. Also, recent reports indicate that oxytocin induces production of PGs in human myometrial cells via upregulation of COX-2. Such a mechanism may explain the sustained release of PGs in uterine tissue, promoting labor. Therefore, there is strong evidence that interfering with the prostaglandin pathway by blocking selectively the contractile FP receptor will delay the progression of labor. A compound able to block the interaction between PGF2α and its receptor, i.e. a PGF2α-receptor antagonist, is therefore assumed to be more efficacious for treating preterm labor than current regimens.
Because of the involvement of PGF2α in birth initiation, several approaches have already been performed to test new PGF2α inhibitors. Indomethacin is a well known prostaglandin inhibitor and has already been tested to study the possible mode of action of prostaglandins (Prostaglandins, 12(6) p. 1053-9 (1976) by Chatterjee A.). In J. Reprod. Fertil., 116(1), p. 103-111 (1999) Williams B. J. et al observed that flunixin meglumin disrupted the normal 13,14-dihydro-15-keto prostaglandin F2α profile but did not abolish prostaglandin synthesis completely or delay the onset of labor in treated animals. Mattos R. et al (Rev. Reprod., 5(1), p. 3845 (2000) use polyunsaturated fatty acids such as linoleic, linolenic, eicosapentaenoic and docosahexaenoic acids which may inhibit prostaglandin F2α.
Recently, a phenol derivative known as p38 inhibitor (4-[5-(4-fluorophenyl)-4-(4-pyridyl)-imidazol-2-yl]phenol) has been tested and it has been observed that said compound inhibited both prostaglandin F2α production and COX-2 expression induced by stimulation with IL-1β (Biochem. Biophys. Res. Common., 288(5), p. 1155-1161 (2001) by Chuo-ku Chiba).
Tsumura & Co proposed prostaglandin F2α inhibitor active to relax the smooth muscle of uterine and effective for the remedy of abdominal pain caused by abortion, premature labor and dysfunction, by using a phtalide derivative as an active component (JP-01050818).
In their patent (U.S. Pat. No. 6,271,201), Board of Regents, the University of Texas System discloses a method for regulating placental cell production of thromboxane and PGF2α comprising treating placenta cells with a pharmacologically effective amount of insulin-like growth factor I sufficient to inhibit thromboxane and prostaglandin F2α production without affecting prostacyclin or prostaglandin E2 production.
Furthermore, literature suggests that prostaglandins stimulate the proliferation of human colon carcinoma cells in vitro (Biochemica at Biophysica Acta 1258/2, p. 215-223 (1995)). It is known that increased expression of cyclooxygenase (COX) and over-production of prostaglandins (PGs) have been implicated in the development and progression of colorectal cancer (Cancer Research, Vol 58, Issue 11 p. 2323-2327). It has been disclosed in the patent literature that a decrease in a specific prostanoid metabolite, PGF2α, could account for the beneficial effects of NSAIDS in the prevention and treatment of colorectal cancer (WO 02/058546 filed by The Arizona Board of Regents).